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. 2020 Oct 16;6(4):229. doi: 10.3390/jof6040229

Metabolites from Clonostachys Fungi and Their Biological Activities

Peipei Han 1, Xuping Zhang 1, Dan Xu 1, Bowen Zhang 1, Daowan Lai 1, Ligang Zhou 1,*
PMCID: PMC7712584  PMID: 33081356

Abstract

Clonostachys (teleomorph: Bionectria) fungi are well known to produce a variety of secondary metabolites with various biological activities to show their pharmaceutical and agrochemical applications. Up to now, at least 229 secondary metabolites, mainly including 84 nitrogen-containing metabolites, 85 polyketides, 40 terpenoids, and 20 other metabolites, have been reported. Many of these compounds exhibit biological activities, such as cytotoxic, antimicrobial, antileishmanial, antimalarial activities. This mini-review aims to summarize the diversity of the secondary metabolites as well as their occurrences in Clonostachys fungi and biological activities.

Keywords: secondary metabolites, Clonostachys fungi, Bionectria, Gliocladium, Nectria, structural diversity, biological activities

1. Introduction

The fungal genus Clonostachys (formerly named Gliocladium), teleomorph Bionetria (formerly named Nectria or Nectriopsis), belongs to the family Bionectriaceae of Sordariomycetes in Ascomycota [1]. The Clonostachys fungi are widely distributed all over the world. They are saprotrophs, destructive mycoparasites, lichenicoles, or inhabitants of recently dead trees and decaying leaves. At present, there are about 44 species in the genus Clonostachys [1], and among them, about 18 species have been studied for their secondary metabolites, including B. byssicola, B. ochroleuca, B. pityrodes, C. candelabrum, C. compactiuscula, C. rogersoniana, C. rosea, G. roseum, N. coccinea, N. coryli, N. erubescens, N. fuckeliana, N. galligena, N. haematococca, N. inventa, N. lucida, N. pseudotrichia, and N. viridescens.

Clonostachys fungi are abundant in many classes of secondary metabolites, mainly including nitrogen-containing compounds, polyketides, and terpenoids. Many metabolites exhibit biological activities, such as antimicrobial, insecticidal, nematocidal, antiparasitic, phytotoxic and cytotoxic activities. Until now, secondary metabolites of Clonostachys fungi and their biological activities have not been reviewed. This mini-review describes the classification, occurrences, and biological activities of the secondary metabolites from Clonostachys fungi.

2. Nitrogen-Containing Metabolites and Their Biological Activities

The nitrogen-containing metabolites from Clonostachys fungi mainly include linear oligopeptides, cyclopeptides, and piperazines. The nitrogen-containing metabolites, their isolated Clonostachys fungi and biological activities are shown in Table 1.

Table 1.

Nitrogen-containing metabolites in Clonostachys fungi and their biological activities.

Metabolite Class Metabolite Name Fungal Species Biological Activity Ref.
Linear oligopeptides Clonostachin (1) Clonostachys sp. F5898 Inhibition on platelet aggregation [2]
Bionectria sp. MSX 47401 - [3]
Clonostachin B (2) Bionectria sp. MSX 47401 - [3]
Pullularin F (3) Bionectria ochroleuca - [4]
Cyclopeptides Argadin (4) Clonostachys sp. FO-7314 Inhibitory activity on chitinase [5]
Argifin (5) Gliocladium sp. FTD-0668 Inhibitory activity on chitinase [6,7]
Arthrichitin (6) Nectria sp. - [8]
Antifungal activity on the yeasts [9]
Clonostachysin A (7) Clonostachys rogersoniana Anti-dinoflagellate activity [10]
Clonostachysin B (8) Clonostachys rogersoniana Anti-dinoflagellate activity [10]
Cyclo-(Gly-D-Leu-D-allo-Ile-L-Val-L-Val-D-Trp-β-Ala) (9) Clonostachys rosea Cytotoxic activity [11]
Cyclo-(Gly-D-Leu-L-Val-L-Val-L-Val-D-Trp-β-Ala) (10) Clonostachys rosea - [11]
Cyclo-(Gly-D-Leu-D-allo-Ile-D-allo-Ile-L-Val-D-Trp-β-Ala) (11) Clonostachys rosea - [11]
Cyclosporin A (12) Nectria sp. F-4908 - [12]
Immunosuppressive and antifungal activities [13]
Cyclosporin C (13) Nectria sp. F-4908 - [12]
Immunosuppressive and antifungal activities [13]
IB-01212 (14) Clonostachys sp. ESNA-A009 Cytotoxic activity [14]
Antileishmanial activity [15]
Pullularin A (15) Bionectria ochroleuca Cytotoxic activity [4]
Pullularin C (16) Bionectria ochroleuca Cytotoxic activity [4]
Pullularin E (17) Bionectria ochroleuca - [4]
Piperazines Bionectin A (18) Bionectria byssicola F120 Antibacterial activity [16]
Bionectin B (19) Bionectria byssicola F120 Antibacterial activity [16]
Bionectin C (20) Bionectria byssicola F120 - [16]
Bionectin D (21) Bionectria sp. Y1085 Antibacterial activity [17]
Bionectin E (22) Bionectria sp. Y1085 Antibacterial activity [17]
3,6-Bis(methylthio)-cyclo(alanyltryptophyl) (23) Nectria inventa Trypanocidal activity [18]
Chaetocin (24) Nectria inventa Trypanocidal activity [18]
Chetoseminudin B (25) Nectria inventa Trypanocidal activity [18]
Clonocoprogen A (26) Clonostachys compactiuscula FKR-0021 Antimalarial activity [19]
Clonocoprogen B (27) Clonostachys compactiuscula FKR-0021 Antimalarial activity [19]
Clonocoprogen C (28) Clonostachys compactiuscula FKR-0021 Antimalarial activity [19]
N14-Plmitoylcoprogen (29) Clonostachys compactiuscula FKR-0021 Antimalarial activity [19]
Cyclo (L-Pro-L-Leu) (30) Bionectria sp. Y1085 - [17]
Dioxopiperazine (31) Bionectria sp. Y1085 - [17]
Gliocladicillin A (32) Bionectria sp. Y1085 - [17]
Gliocladicillin C (33) Bionectria sp. Y1085 Antibacterial activity [17]
Clonostachys rogersoniana Cytotoxic activity [20]
Gliocladin A (34) Glicladium roseum OUPS-N132 - [21]
Gliocladin B (35) Glicladium roseum OUPS-N132 - [21]
Gliocladin C (36) Glicladium roseum OUPS-N132 Cytotoxic activity [21]
Gliocladium roseum YMF1.00133 Antinematodal activity [22]
Gliocladine A (37) Gliocladium roseum 1A Antinematodal activity [23]
Gliocladine B (38) Gliocladium roseum YMF1.00133 Antinematodal activity [23]
Bionectria sp. Y1085 - [17]
Gliocladine C (39) Gliocladium roseum 1A Antinematodal activity [23]
Gliocladine D (40) Gliocladium roseum 1A Antinematodal activity [23]
Gliocladine E (41) Gliocladium roseum 1A Antinematodal activity [23]
Glioclatine (42) Gliocladium roseum YMF1.00133 Antinematodal activity [24]
Glioperazine (43) Gliocladium sp. OUPS-N132 - [21]
Bionectria byssicola F120 - [25]
Clonostachys rosea - [11]
Glioperazine B (44) Bionectria byssicola F120 Antimicrobial activity [25]
Glioperazine C (45) Bionectria byssicola F120 - [25]
Haematocin (46) Nectria haematococca Antifuangl activity [26]
Lasiodipline D (47) Bionectria sp. Y1085 - [17]
Sch52900 (48) Gliocladium roseum 1A Antinematodal activity [23]
Sch52901 (49) Gliocladium roseum 1A Antinematodal activity [23]
Verticillin A (50) Gliocladium roseum 1A Antinematodal activity [23]
Bionectria sp. Y1085 - [17]
11′-Deoxyverticillin A (51) Gliocladium roseum 1A Antinematodal activity [23]
11,11′-Dideoxyverticillin A (52) Bionectria sp. Y1085 - [17]
Verticillin B (53) Nectria inventa Trypanocidal activity [18]
Verticillin D (54) Bionectria byssicola F120 - [16]
Bionectria ochroleuca Cytotoxic activity [4]
Clonostachys rosea Cytotoxic activity [11]
Verticillin G (55) Bionectria byssicola F120 Antibacterial activity [25]
Verticillin H (56) Bionectriaceous strains MSX 64546 and MSX 59553 Cytotoxic activity [27]
Other nitrogen-containing metabolites N-Benzyl-3-phenyllactamide (57) Clonostachys compactiuscula FKR-0021 - [19]
N-Benzyl-3-phenylpropanamide (58) Clonostachys compactiuscula FKR-0021 - [19]
Bionectriamine A (59) Co-cultivation of Bionectria sp. with Bacillus subtilis or Streptomyceslividans - [28]
Bionectriamine B (60) Co-cultivation of Bionectria sp. with Bacillus subtilis or Streptomyceslividans - [28]
Cinnacidin (61) Nectria sp. DA060097 Phytotoxic activity [29]
Clonostalactam (62) Clonostachys rosea - [11]
Cytochalasin D (63) Nectria pseudotrichia Weak leishmanicidal activity [30]
Fusarin C (64) Nectria coccinea A56-9 Antifungal activity [31]
(5Z)-Fusarin C (65) Nectria coccinea A56-9 Antifungal activity [31]
(7Z)-Fusarin C (66) Nectria coccinea A56-9 Antifungal activity [31]
Gliocladiosin A (67) verM disruption mutant of Clonostachys rogersoniana Antibacterial activity [32]
Gliocladiosin B (68) verM disruption mutant of Clonostachys rogersoniana Antibacterial activity [32]
Rogersonin A (69) verG disruption mutant of Clonostachys rogersoniana - [33]
Rogersonin B (70) verG disruption mutant of Clonostachys rogersoniana - [33]
Ilicicolin H (71) Nectria sp. B-13 - [34]
(S)-Phenopyrrozin (72) Bionectria sp. - [28]
(S)-p-Hydroxyphenopyrrozin (73) Bionectria sp. - [28]
1,2-Dihydrophenopyrrozin (74) Bionectria sp. - [28]
1,2-Dehydrovirgineone (75) Bionectria sp. MSX 47401 Antibacterial activity [3]
Virgineone (76) Bionectria sp. MSX 47401 Antibacterial and antifungal activities [3]
Virgineone aglycone (77) Bionectria sp. MSX 47401 Antibacterial activity [3]
Indole-3-acetic acid (78) Bionectria sp. Y1085 - [17]
L-Tryptophan (79) Bionectria sp. Y1085 - [17]
FR-900483 (80) Nctria lucida F-4490 Immunostimulatory activity [35]
Bostrycoidin (81) Nectria haematococca - [36]
5-Deoxybostrycoidin (82) Nectria haematococca - [37]
Penicolinate A (83) Bionectria sp. Cytotoxic activity [28]
Scorpinone (84) Nectria pseudotrichia - [38]
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2.1. Linear Oligopeptides

The oligopeptides from fungi include linear and cyclic peptides. Two linear tetradecapeptides, named clonostachin (1) and clonostachin B (2) were isolated from Clonostachys fungi (Figure 1). Clonostachin (1) was first isolated from Clonostachys sp. F5898, and both clonostachin (1) and clonostachin B (2) were then isolated from Bionectria sp. MSX 47401, and each oligopeptide contained an N-terminal acetyl group and a C-terminal mannitol unit [3]. Clonostachin (1) inhibited ADP-induced aggregation of human platelets by 80% at 150 μM [2]. Pullularin F (3) was isolated from the endophytic fungus Bionectria ochroleuca from the mangrove plant Sonneratia caseolaris [4].

Figure 1.

Figure 1

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Linear oligopeptides isolated from Clonostachys fungi.

2.2. Cyclopeptides

Cyclopeptides are cyclic compounds formed mainly by the amide bonds between either proteinogenic or non-proteinogenic amino acids [13,39]. The structures of the cyclopeptides isolated from Clonostachys fungi are shown in Figure 2.

Figure 2.

Figure 2

Figure 2

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Cyclopeptides isolated from Clonostachys fungi.

Argadin (4), a cyclic pentapeptide, was isolated from Clonostachys sp. FO-7314. It showed inhibitory activity against blowfly (Lucilia cuprina) chitinase with IC50 values of 150 nM at 37 °C and 3.4 nM at 20 °C, respectively [5]. Another cyclic pentapeptide, namely argifin (5), from Gliocladium sp. also exhibited inhibitory activity against blowfly chitinase [6,7].

Arthrichitin (6) was a cyclic tetradepsipeptide isolated from Nectria sp. [8]. This lipodepsipeptide was also isolated from other fungi to show inhibitory activity on the yeasts Schizosaccharomyces pombe and Rhodotorula glutinis [9].

Clonostachysins A (7) and B (8) were two cyclic nonapeptides isolated from Clonostachys rogersoniana. They exhibited a selectively inhibitory effect on a dinoflagellate Prorocentrum micans at 30 μM but had no effect on other microalgae and bacteria, even at 100 μM [10].

Three cyclic heptapeptides, named cyclo-(Gly-D-Leu-D-allo-Ile-L-Val-L-Val-D-Trp-β-Ala) (9), cyclo-(Gly-D-Leu-L-Val-L-Val-L-Val-D-Trp-β-Ala) (10), and cyclo-(Gly-D-Leu-D-allo-Ile-D-allo-Ile-L-Val-D-Trp-β-Ala) (11), were isolated from the soil-derived fungus Clonostachys rosea. Among them, cyclo-(Gly-D-Leu-D-allo-Ile-L-Val-L-Val-D-Trp-β-Ala) (9) exhibited significant cytotoxic activity against the L5178Y mouse lymphoma cell line with an IC50 value of 4.1 μM [11].

Two cyclic undecapeptides cyclosporins A (12) and C (13) were isolated from Nectria sp. F-4908 [12]. They showed immunosuppressive and antifungal activities [13].

IB-01212 (14), a cyclic hexadepsipeptide from the marine fungus Clonostachys sp. ESNA-A009, exhibited antitumor activity on the cell lines of LN-caP (prostate cancer), SK-BR3 (breast cancer), HT29 (colon cancer), and HeLa (cervix cancer) [14]. In addition, IB-01212 (14) showed antileishmanial activity [15].

Three cyclic hexadepsipeptides pullularins A (15), C (16) and E (17) were isolated from the endophytic fungus Bionectria ochroleuca. Both pullularins A (15) and C (16) showed moderate cytotoxic activity against mouse lymphoma cells [4]. Furthermore, pullularin A (15) from another fungus Pullularia sp. BCC 8613 exhibited antimalarial, antiviral and antitubercular activities [40].

2.3. Piperazines

The piperazines (also called 2,5-diketopiperazines) are formed by the condensation of two amino acids [41]. Piperazines are the common nitrogen-containing metabolites as monomers or dimers in Clonostachys fungi, and most of them contain disulfide bonds. The structures of piperazines isolated from Clonostachys fungi are shown in Figure 3.

Figure 3.

Figure 3

Figure 3

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Piperazines isolated from Clonostachys fungi.

Bionectins A (18), B (19) and C (20), and verticillin D (54) were isolated from the liquid fermentation cultures of Bionectria byssicola F120. Both bionectins A (18) and B (19) exhibited antibacterial activity against Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA) and quinolone-resistant Staphylocossu aureus (QRSA), with MIC values of 10-30 μg/mL [16]. Bionectins D (21) and E (22), cyclo (L-Pro-L-Leu) (30), dioxopiperazine (31), and gliocladicillins A (32) and C (33) were isolated from Bionectria sp. Y1085. Among them, bionectins D (21) and E (22), as well as gliocladicillin C (33) showed antibacterial activity on Escherichia coli, Staphylococcus aureus and Salmnonella typhimurium [17].

Four diketopiperazines: 3,6-bis(methylthio)-cyclo(alanyltryptophyl) (23), chaetocin (24), chetoseminudin B (25) and verticillin B (53) from deep water marine-derived fungus Nectria inventa showed trypanocidal activity on Trypanosoma brucei [18].

Four siderophore analogs, clonocoprogens A (26), B (27) and C (28) and N14-plmitoylcoprogen (29), were isolated from Clonostachys compactiuscula FKR-0021. They exhibited antimalarial activity against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum strains, with IC50 values ranging from 1.7 μM to 9.9 μM [19].

Gliocladins A (34), B (35) and C (36) and glioperazine (43) were isolated from Gliocladium sp. originally separated from the sea hare (Aplysia kurodai). Gliocladin C (36), which was a structurally unique trioxopiperazine, showed significant cytotoxicity against the murine P388 lymphocytic leukemia cells with IC50 value of 2.4 μg/mL [21]. Gliocladin C (36) from Gliocladium roseum YMF1.00133 was further screened to show antinematodal activity against nematodes Panagrellus redivivus, Caenothabditis elegans and Bursaphelenchus xylophilus [22].

Nine epipolysulfanyldioxopiperazines isolated from Gliocladium roseum 1A displayed antinematodal activity against Caenorhabditis elegans and Panagrellus redivivus. The dimers, including gliocladine A (37), gliocladine B (38), sch52900 (48), sch52901 (49), verticillin A (50), and 11′-deoxyverticillin A (51) are more active than the monomers with the indole moiety, namely, gliocladines C (39), D (40) and E (41). Among them, 11′-Deoxyverticillin A (51) was the most potent antinematodal compound [23].

Three dioxopiperazines: glioperazine (43), glioperazine B (44) and glioperazine C (45) were isolated from Bionectria byssicola F120. Among them, glioperazine B (44) showed weak antibacterial activity against Staphylococcus aureus [25].

Haematocin (46) was isolated from the culture broth of Nectria haematococca, the blight disease pathogen of ornamental plants. Haematocin (46) inhibited the germ-tube elongation and spore germination of rice blast pathogen Pyricularia oryzae at the IC50 values of 30 and 160 μg/mL, respectively [26].

Verticillins were the dimeric epipolythiodioxopiperazines widely distributed in Bionectriaceous fungi. Most of verticillins exhibited cytotoxic activities [11,27]. Among them, verticillin A (50) showed obviously cytotoxic acitivity by causing apoptosis and reducing tumor burden in high-grade serious ovarian cancer by inducing DNA damage [42]. Verticillins D (54) and G (55) were isolated from Bionectria byssicola, and verticillin G (55) was screened to have antibacterial activity on Staphylococcus aureus with MIC values of 3–10 μg/mL [25]. Verticillin D (54) from the endophytic fungus Bionectria ochroleuca showed pronounced cytotoxic activity against mouse lymphoma cells [4].

2.4. Other Nitrogen-Containing Metabolites

The structures of the other nitrogen-containing metabolites, including amides and amines isolated from Clonostachys fungi are shown in Figure 4.

Figure 4.

Figure 4

Figure 4

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Other nitrogen-containing metabolites isolated from Clonostachys fungi.

Both N-benzyl-3-phenyllactamide (57) and N-benzyl-3-phenylpropanamide (58) were isolated from Clonostachys compactiuscula FKR-0021 [19].

Fusarin C (64), (5Z)-fusarin C (65) and (7Z)-fusarin C (66) were isolated from Nectria coccinea A56-9. They showed antifungal activity against Pyricularia oryzae by inhibiting dihydroxynaphthalene-melanin biosynthesis [31].

Gliocladiosins A (67) and B (68), the dipeptides conjugated with macrolides, were isolated from an O-methyltransferase gene, verM disruption mutant of the Cordycep-colonizing fungus Clonostachys rogersoniana. These two compounds showed moderate antibacterial activity on Klebsiella pneumonia and Bacillus subtlilis [32]. Similarly, rogersonins A (69) and B (70) were two indole-polyketide hydrids isolated from verG disruption mutant of Clonostachys rogersoniana [33]. Blocking the biosynthesis of secondary metabolites through the disuption of the biosynthesis-related genes provide a method to activate cryptic or silent secondary metabolites in fungi.

Three tetramic acid derivatives namely 1,2-dehydrovirgineone (75), virgineone (76) and virgineone aglycone (77) were isolated from Bionectria sp. MSX 47401. They showed obviously antibacterial activity against Staphylococcus aureus and several MRSA isolates. In addition, virgineone (76) showed moderate antifungal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus niger with an MIC value of 14.4 μg/mL [3].

FR-900483 (80), which was called nectrisine or 3-(R)-4-(R)-dihydroxy-5-(R)-hydroxymethyl-1-pyrroline, was an immunoactive substance produced by Nectria lucida F-4490. FR-900483 (80) could restore the capacity of immunosuppressed mice to produce antibody against sheep red blood cells [35].

Penicolinate A (83) was induced from the endophytic fungus Bionectria sp. through bacterial co-culture. Penicolinate A (83) exhibited potent cytotoxic activity against the human ovarian cancer cell line A2780 with an IC50 value of 4.1 μM [28].

3. Polyketides and Their Biological Activities

A variety of polyketides occur widely in the Clonostachys fungi. According to the structure characteristics, these metabolites were classifed into aromatic, alipahtic and mixed biogenic polyketides [43]. The aromatic polyketides mainly include pyranones, quinones, sorbicillinoids, and others. The polyketides, their isolated Clonostachys fungi and biological activities are shown in Table 2.

Table 2.

Polyketides in Clonostachys fungi and their biological activities.

Metabolite
Class		 Metabolite Name Fungal Species Biological Activity Ref.
Pyranones AGI-7 (85) Bionectria sp. MSX 47401 - [3]
Alternariol (86) Clonostachys rosea YRS-06 - [44]
Alternariol 5-O-methyl ether (87) Clonostachys rosea YRS-06 - [44]
Cephalochromin (88) Nectria viridescens - [45]
Cytotoxic activity [46]
Coniochaetone G (89) Clonostachys compactiuscula FKR-0021 - [19]
Citreoisocoumarinol (90) Nectria sp. HN001 Inhibitory activity on α-glucosidase [47]
12-Epicitreoisocoumarinol (91) Nectria sp. HN001 - [47]
Citreoisocoumarin (92) Nectria sp. HN001 Inhibitory activity on α-glucosidase [47]
6,8-Dihydroxyisocoumarin
-3-carboxylic acid (93)		 Co-cultivation of Bionectria sp. with Bacillus subtilis or Streptomyceslividans - [28]
Macrocarpon C (94) Nectria sp. HN001 Inhibitory activity on α-glucosidase [47]
3-(3-Chloro-2-hydroxypropyl)-8-hydroxy-6-methoxyisochromen-1-one (95) Clonostachys sp. AP4.1 - [48]
Dichlorodiaportin (96) Clonostachys sp. AP4.1 - [48]
Mellein (97) Nectria fuckeliana - [49]
3,4-Dimethyl-6,8-dihydroxyisocoumarin (98) Nectria pseudotrichia 120-1NP - [50]
Nectriapyrone A (99) Nectria pseudotrichia 120-1NP - [50]
Nectriapyrone B (100) Nectria pseudotrichia 120-1NP - [50]
(S)-4-Methoxy-6-pentanoyl-5,6-dihydro-2H-pyran-2-one (101) Nectria sp. - [51]
Necpyrone A (102) Nectria sp. - [51]
Necpyrone B (103) Nectria sp. - [51]
Necpyrone C (104) Nectria sp. - [51]
Necpyrone D (105) Nectria sp. - [51]
Necpyrone E (106) Nectria sp. - [51]
LL-P880α (107) Nectria sp. - [51]
LL-P880β (108) Nectria sp. - [51]
(1S, 2R)-1-Hydroxy-1-((S)-4-methoxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)-pentan-2-yl acetate (109) Nectria sp. - [51]
LL-P880γ (110) Nectria sp. - [51]
PC-2 (111) Nectria sp. - [51]
Quinones Anhydrofusarubin lactone (112) Nectria haematococca - [52]
Aurantiogliocladin (113) Clonostachys candelabrum - [53]
2,5-Dimethyoxy-3,6-dimethyl-1,4-benzoquinone (114) Nectria coryli Antibacterial activity [54]
Nectria fuckeliana - [49]
Fusarubin (115) Nectria haematococca - [36]
4-Deoxyfusarubin (116) Nectria haematococca - [55]
4-Deoxyanhydrofusarubin (117) Nectria haematococca - [55]
5-Deoxyfusarubin (118) Nectria haematococca - [55]
5-Deoxyanhydrofusarubin (119) Nectri haematococca - [55]
Fusarubinoic acid (120) Nectria haematococca - [56]
13-Hydroxynorjavanicin (121) Nectria haematococca - [56]
Herbarin (122) Nectria pseudotrichia 120-1NP Antibacterial and phytotoxic activities [50]
Nectria pseudotrichia Cytotoxic activity [38]
O-Methylherbarin (123) Nectria pseudotrichia 120-1NP Cytotoxic activity [50]
Dehydroherbarin (124) Nectria pseudotrichia Cytotoxi activity [38]
2-Acetoxyl-5,7-dimethoxy-3-methyl-1,4-naphthoquinone (125) Nectria pseudotrichia Cytotoxic activity [38]
Pseudonectrin A (126) Nectria pseudotrichia Cytotoxic activity [38]
Pseudonectrin B (127) Nectria pseudotrichia Cytotoxic activity [38]
Pseudonectrin C (128) Nectria pseudotrichia Cytotoxic activity [38]
Pseudonectrin D (129) Nectria pseudotrichia - [38]
Nectriafurone (130) Nectria haematococca - [52]
Nectriaquinone A (131) Nectria pseudotrichia 120-1NP Cytotoxic activity [50]
Nectriaquinone B (132) Nectria pseudotrichia 120-1NP Antibacterial and cytotoxic activities [50]
P-Toluquinone (133) Nectria erubescens - [57]
Sorbicillinoids Sorbicillin (134) Clonostachys rosea YRS-06 - [44]
Dihydrotrichodimer ether A (135) Clonostachys rosea YRS-06 Antibacterial activity [44]
Dihydrotrichodimer ether B (136) Clonostachys rosea YRS-06 Antibacterial activity [44]
Tetrahydrotrichodimer ether (137) Clonostachys rosea YRS-06 - [44]
Dihydrotrichodimerol (138) Clonostachys rosea YRS-06 Antibacterial activity [44]
Tetrahydrotrichodimerol (139) Clonostachys rosea YRS-06 Antibacterial activity [44]
Trichodimerol (140) Clonostachys rosea YRS-06 - [44]
Other polyketides 3,5-Dihydroxyfuran-2(5H)-one (141) Gliocladium roseum 1A - [23]
Clonostachys rosea - [11]
Sapinofuranone B (142) Gliocladium roseum 1A - [23]
Clonostachys rosea - [11]
(-)-Vertinolide (143) Clonostachys rosea B5-2 - [58]
(-)-Dihydrovertinolide (144) Clonostachys rosea B5-2 Phytotoxic activity [58]
Clonostachydiol (145) Clonostachys cylindrospora FH-A 6607 Anthelmintic activity [59]
Bionectriol A (146) Bionectria sp. - [60]
Bionectriol B (147) Bionectria ochroleuca - [61]
Bionectriol C (148) Bionectria ochroleuca Antifungal activity [61]
Bionectriol D (149) Bionectria ochroleuca - [61]
Rogerson A (150) Clonostachys rogersoniana - [62]
Rogerson B (151) Clonostachys rogersoniana - [62]
Nectriacid A (152) Nectria sp. HN001 - [47]
Nectriacid B (153) Nectria sp. HN001 Inhibitory activity on α-glucosidase [47]
Nectriacid C (154) Nectria sp. HN001 Inhibitory activity on α-glucosidase [47]
Curvularin (155) Clonostachys compactiuscula FKR-0021 - [19]
α,β-Dehydrocurvularin (156) Nectria glligena Cytotoxic and phytotoxic activities [63]
Nectriatone B (157) Nectria sp. B-13 - [64]
Nectriatone C (158) Nectria sp. B-13 - [64]
TMC-151A (159) Clonostachys rosea - [65]
Gliocladium catenulatum Moderate cytotoxicity to tumor cells [66]
Bionectria ochroleuca - [67]
TMC-151B (160) Clonostachys rosea - [67]
Gliocladium catenulatum Moderate cytotoxicity to tumor cells [66]
TMC-151C (161) Clonostachys rosea - [67]
Gliocladium catenulatum Moderate cytotoxicity to tumor cells [66]
TMC-151D (162) Clonostachys rosea - [67]
Gliocladium catenulatum Moderate cytotoxicity to tumor cells [66]
TMC-151E (163) Clonostachys rosea - [67]
Gliocladium catenulatum Moderate cytotoxicity to tumor cells [66]
Bionectria ochroleuca Antifungal activity [61]
TMC-151F (164) Clonostachys rosea - [67]
Gliocladium catenulatum Moderate cytotoxicity to tumor cells [66]
Bionectria ochroleuca Antifungal activity [61]
TMC-154 (165) Gliocladium roseum - [67]
TMC-171A (166) Gliocladium roseum - [67]
TMC-171B (167) Gliocladium roseum - [67]
TMC-171C (168) Gliocladium roseum - [67]
Usnic acid (169) Bionectria ochroleuca Bo-1 Antibacterial activity [68]
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3.1. Pyranones

Pyranones (also named pyrones) from fungi include α-, β- and γ-pyranones [69]. Most pyranones produced by Clonostachys fungi belong to α-pyranones. Their structures are shown in Figure 5.

Figure 5.

Figure 5

Figure 5

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Pyranones isolated from Clonostachys fungi.

Cephalochromin (88), a bisnaphtho-γ-pyrone, was isolated from Nectria viridescens [45]. This compound was screened to exhibit cytotoxic activity by inducing G0/G1 cell cycle arrest and apoptosis in A549 human non-small-cell lung cancer cells by inflicting mitochondrial disruption [46].

Citreoisocoumarinol (90), citreoisocoumarin (92) and macrocarpon C (94) showed moderate inhibitory activity on α-glucosidase with IC50 values ranging from 300 to 600 µM [47].

Two isocoumarin derivatives, 3-(3-chloro-2-hydroxypropyl)-8-hydroxy- 6-methoxyisochromen-1-one (95) and 3-[(R)-3,3-dichloro-2-hydroxypropyl]- 8-hydroxy-6- methoxy-1H-isochromen-1-one (dichlorodiaportin, 96), were identified from Clonostachys sp. AP4.1 [48].

3.2. Quinones

The quinones isolated from Clonostachys fungi were mainly naphthoquinones except for three p-benzoquinones. Their structures are shown in Figure 6.

Figure 6.

Figure 6

Figure 6

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Quinones isolated from Clonostachys fungi.

2,5-Dimethoxy-3,6-dimethyl-1,4-benzoquinone (114) from Nectria coryli inhibited the growth of Staphylococcus aureus at a concentration of 1 μg/mL [54].

Herbarin (122) and nectriaquinone B (132) isolated from the brown rice culture of Nectria pseudotrichia 120-1NP exhibited antibacterial activities against Staphylococcus aureus and Pseudomonas aeruginosa [50]. Herbarin (122), O-methylherbarin (123), nectriaquinone A (131), and nectriaquinone B (132) displayed cytotoxic activity against human promyelocytic leukemia HL60 cells with IC50 values of 11.9, 1.33, 1.93, and 11.6 μM, respectively. The structure-function relationship elucidated that the higher cytotoxicity of herbarin (122) and nectriaquinone B (132), compared to that of the related compounds O-methylherbarin (123) and nectriaquinone A (131) was attributed to their increased cell membrane permeability due to the presence of the hydroxyl group [38,50]. In addition, herbarin (122) showed a significant inhibition on lettuce seedling growth [50].

Seven naphthoquinones, named pseudonectrins A (126), B (127), C (128), D (129), herbarin (122), dehydroherbarin (124) and 2-acetoxyl-5,7-dimethoxy-3-methyl-1,4-naphthoquinone (125) were isolated from Nectria pseudotrichia. They all showed cytotoxic activity except for pseudonectrin D (129). In addition, pseudonectrins A (126), B (127) and C (128) had a skeleton of pyranonaphthoquinone [38].

3.3. Sorbicillinoids

Sorbicillinoids are important hexaketide metabolites produced by fungi [70]. Six dimeric and one monomeric sorbicillinoids were extracted from culture broth of Clonostachys rosea YRS-06 [44]. Their structures are shown in Figure 7. Dihydrotrichodimer ether A (135), dihydrotrichodimer ether B (136) and tetrahydrotrichodimer ether (137) are rare bisorbicillinoids with a γ-pyrone moiety. Dihydrotrichodimer ether A (135), dihydrotrichodimer ether B (136), dihydrotrichodimerol (138) and tetrahydrotrichodimerol (139) showed antibacterial activity against Bacillus subtilis, Clostridium perfringens, and Escherichia coli [44].

Figure 7.

Figure 7

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Sorbicillinoids isolated from Clonostachys fungi.

3.4. Other Polyketides

The structures of the other polyketides isolated from Clonostachys fungi are shown in Figure 8. These metabolites mainly belong to aliphatic polyketides. Some of them contain a glycosyl group and exist as glycosides.

Figure 8.

Figure 8

Figure 8

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Other polyketides isolated from Clonostachys fungi.

Four α-furanones were obtained. Both 3,5-dihydroxyfuran-2(5H)-one (141) and sapinofuranone B (142) were isolated from Gliocladium roseum 1A [23]. Both (-)-vertinolide (143) and (-)-dihydrovertinolide (144) were isolated from Clonostachys rosea B5-2. (-)-Dihydrovertinolide (144) displayed phytotoxic activity against lettuce seedlings at a concentration of 50 μg/mL [58].

Clonostachydiol (145) was a 14-membered macrodiolide isolated from the fungus Clonostachys cylindrospora (strain FH-A 6607). It exhibited anthelimintic activity against abomasum nematode Haemonchus cortorus in artificially infected lambs [59]. Four stereocenters in clonostachydiol were revised later [71].

Polyketide glycosides bionectriols A (146), B (147) and C (148) were isolated from Bionectria chroleuca [61]. TMC-151E (163), TMC-151F (164) and bionectriol C (148) moderately inhibited Candida albicans biofilm formation with IC50 values of 36.3, 41.0 and 24.1 μM, respectively [61].

Nectriacids B (153) and C (154) showed stronger α-glucosidase inhibitory activity than positive control (acarbose, IC50, 815.3 µM) with IC50 values of 23.5 and 42.3 µM, respectively.

α,β-Dehydrocurvularin (156) from Nectria glligena was proved to be cytotoxic to human lung fibroblasts with IC50 value less than 12 µg/mL. In addition, α,β-dehydrocurvularin (156) significantly reduced radicle length and epicotyl growth in Lactuca sativa at 100 and 200 µg/disk [63].

Both nectriatones B (157) and C (158) were cyclohexanone derivatives from Nectria sp. B-13 [64].

A series of polyketides TMC-151 (159–164), TMC-154 (165) and TMC-171 (166–168) were found exclusively in Gliocladium and Clonostachys species [67]. They contained D-mannopyranoside and D-mannitol or D-arabitol and showed moderate cytotoxicity on several tumor cells [66].

Usnic acid (169) is a unique polyketide from Bionectria ochroleuca Bo-1 which was isolated as an endophytic fungus from rice. It showed antibacterial activity against Xanthomonas oryzae with MIC value of 200 µg/mL [68].

4. Terpenoids and Their Biological Activities

The terpenoids from Clonostachys fungi include monoterpenoids, sesquiterpenoids, diterpenoids, triterpenpoids, polyterpenoids, and meroterpenoids. The terpenoids, along with their isolated Clonostachys fungi and biological activities are shown in Table 3.

Table 3.

Terpenoids in Clonostachys fungi and their biological activities.

Metabolite Class Metabolite Name Fungal Species Biological Activity Ref.
Monoterpenoids Nectriapyrone (170) Nectria sp. HLS206 - [72]
Nectriapyrone C (171) Nectria sp. HLS206 - [72]
Nectriapyrone D (172) Nectria sp. HLS206 - [72]
Sesquiterpenoids 5,6-Dihydroxybisabolol (173) Bionectria sp. MSX 47401 - [3]
Nectrianolin C (174) Nectria pseudotrichia 120-1NP Cytotoxic activity [73]
10-Acetyl trichoderonic acid A (175) Nectria pseudotrichia Leishmanicidal activity [30]
Hydroheptelidic acid (176) Nectria pseudotrichia Leishmanicidal activity [30]
Ophioceric acid (177) Clonostachys compactiuscula FKR-0021 - [19]
Xylaric acid D (178) Nectria pseudotrichia - [30]
Diterpenoids Agathic acid (179) Bionectria sp. - [28]
Nectriatone A (180) Nectria sp. B-13 Cytotoxic activity [64]
Zythiostromic acid C (181) Nectria pseudotrichia 120-1NP - [50]
Triterpentoids Eburicol (182) Clonostachys rosea MMS1090 Cytotoxic activity [74]
Helvolic acid (183) Nectria sp. - [51]
Antimicrobial activity [75,76]
Polyterpenoids Glisoprenin A (184) Gliocladium sp. FO-1513 Inhibition on acyl-CoA:cholesterol acyltransferase [77]
Glisoprenin B (185) Gliocladium sp. FO-1513 Inhibition on acyl-CoA:cholesterol acyltransferase [77]
Glisoprenin C (186) Gliocladium roseum HA190-95 Inhibition on appressorium formation of Magnaporthe grisea [78]
Glisoprenin D (187) Gliocladium roseum HA190-95 Inhibition on appressorium formation of Magnaporthe grisea [78]
Glisoprenin E (188) Gliocladium roseum HA190-95 Inhibition on appressorium formation of Magnaporthe grisea [78]
Bionectin F (189) Bionectria sp. Y1085 - [17]
Meroterpenoids Ascochlorin = Ilicicolin D = LL-Z 1272γ (190) Nectria lucida - [79]
Nectria sp. Antifungal activity [8]
Nectria sp. B-13 - [34]
Nectria sp. B-13 Cytotoxic activity [64]
Dechloroilicicolin D = Cylindrol (191) Nectria sp. Antifungal activity [8]
3-Bromoascochlorin (192) Nectria coccinea - [80]
Chloronectrin (193) Nectria coccinea - [80]
Deacetylchloronectrin (194) Nectria sp. B-13 - [34]
Dechlorodihydroascochlorin = Dechloro-12,13-dihydroascochlorin = LL-Z 1272ε (195) Nectria lucida - [79]
Nectria sp. B-13 - [34]
Ilicicolin C = LL-Z 1272δ (196) Nectria sp. B-13 - [34]
Nectria galligena Inhibitory activity on AChE and α-glucuronidase [63]
Ilicicolin E = 8′,9′-Dehydroascochorin = Cylindrochlorin (197) Nectria sp. B-13 Antibacterial activity [34]
Nectria sp. Antifungal activity [8]
Nectria sp. B-13 Cytotoxic and antibacterial activities [64]
Nectria galligena Inhibitory activity on AChE and α-glucuronidase [63]
Ilicicolin F = LL-Z 1272ζ (198) Nectria sp. B-13 - [34]
Nectria galligena - [63]
Nectria sp. Antifungal activity [8]
Nectrianolin A (199) Nectria pseudotrichia 120-1NP Cytotoxic activity against HL60 and HeLa cells [73]
Nectrianolin B (200) Nectria pseudotrichia 120-1NP Cytotoxic activity against HL60 and HeLa cells [73]
Ascofuranone (201) Nectria sp. Antifungal activity [8]
Chalmicrin (202) Nectria sp. HLS206 - [81]
Colletochlorin B (203) Nectria sp. B-13 - [34]
Nectria galligena Inhibitory activity on AChE and α-glucuronidase [63]
Colletorin B (204) Nectria galligena - [63]
Ilicicolin A (205) Nectria sp. B-13 - [34]
Ilicicolin B = LL-Z 1272β (206) Nectria coccinea - [80]
Nectria lucida - [79]
MBJ-0009 (207) Nectria sp. f26111 Cytotoxic activity [82]
MBJ-0010 (208) Nectria sp. f26111 Cytotoxic activity [82]
Taxol = Paclitaxel (209) Gliocladium sp. Cytotoxicity on cancer cells [83]
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4.1. Monoterpenoids

Three monoterpenoids named nectriapyrone (170), nectriapyrones C (171) and D (172) with α–pyrone skeletons were isolated from the fungus Nectria sp. HLS206 associated with the marine sponge Gelliodes carnosa [72]. Their structures are shown in Figure 9.

Figure 9.

Figure 9

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Monoterpenoids isolated from Clonostachys fungi.

4.2. Sesquiterpenoids

The structures of the sesquiterpenoids isolated from Clonostachys fungi are shown in Figure 10. Nectrianolin C (174) from Nectria pseudotrichia 120-1NP exhibited cytotoxic activity against HL60 and HeLa cells [73].

Figure 10.

Figure 10

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Sesquiterpenoids isolated from Clonostachys fungi.

Three sesquiterpene acids: 10-acetyl trichoderonic acid A (175), hydroheptelidic acid (176), and xylaric acid D (178) were isolated from the endophytic fungus Nectria pseudotrichia of the tree Caesalpinia echinata. The 10-Acetyl trichoderonic acid A (175) and hydroheptelidic acid (176) showed strong antileishmanial activity [30].

4.3. Diterpenoids

Three diterpenoids (179–181) have been isolated from Clonostachys fungi so far (Figure 11). Nectriatone A (180) from Nectria sp. B-13 exhibited cytotoxic activity against the human cancer cell lines, including SW1990, HCT-116, MCF-7 and K562 [64].

Figure 11.

Figure 11

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Diterpenoids isolated from Clonostachys fungi.

4.4. Triterpenoids

Only two triterpenoids (182, 183) were described with their structures shown in Figure 12. Eburicol (182) exhibited cytotoxic activities on the four human cancer cell lines, which included MCF-7, MDA-MB-231, NSCLC-N6-L16 and A549 cells with IC50 values lower than 40 µM [74]. Helvolic acid (183) was a nortriterpenoid isolated from many other fungi, such as Pichia guilliermondii [75], and Aspergillus fumiatus [76]. This compound exhibited obvious antimicrobial activity [75,76].

Figure 12.

Figure 12

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Triterpenoids isolated from Clonostachys fungi.

4.5. Polyterpenoids

The polyterpenes in Clonostachys fungi were tetraterpenes or pentaterpenes whose structures are shown in Figure 13. Five polyprenol polyterpenoids, glioprenins A–E (184–188) were isolated from Gliocladium species [77,78]. Glisoprenins A (184) and B (185) from Gliocladium sp. FO-1513 showed inhibitory activity on acyl-CoA:cholesterol acyltransferase [77], and glioprenins C (186), D (187) and E (188) from the submerged cultures of Gliocladium roeum HA190-95 showed inhibition on appressorium formation of Magnaporthe grisea [78].

Figure 13.

Figure 13

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Polyterpenoids isolated from Clonostachys fungi.

Bionectin F (189), another polyprenol polyterpenoid, was isolated from the endophytic fungus Bionectria sp. Y1085 [17].

4.6. Meroterpenoids

Meroterpenoids are metabolites that are partially derived from terpenoid biosynthetic pathways. The structures of meroterpenoids isolated from Clonostachys fungi are shown in Figure 14.

Figure 14.

Figure 14

Figure 14

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Meroterpenoids isolated from Clonostachys fungi.

Ascochlorin (also named illicolin D or LL-Z 1272γ, 190), dechlorodihydroascochlorin (195) and ilicicolin B (or called LL-Z 1272β, 206) were isolated from Nectria sp. [79].

Ilicicolins D (190), E (197) and F (198), dechloroilcicolin D (191) and ascofuranone (201) showed antifungal activity against plant pathogens Neurospora crassa, Botrytis cinerea, Fusariumculmorum, Pyricularia oryzae, and Penicillium digitarum [8].

Ilicicolins C (196) and E (197), and colletochlorin B (203) from the phytopathogenic fungus Nectria galligena displayed inhibitory activity toward acetylcholinesterase (AChE) and α-glucuronidase with IC50 values of 30-36 µg/mL in the AChE assay and 32-43 µg/mL in the α-glucuronidase test [63].

Ilicicolin E (197) obtained from soil-derived fungus Nectria sp. B-13 showed antibacterial activities against Escherichia coli, Bacillus subtilis and Staphylococcus aureus with MIC values of 4.0, 2.0 and 4.0 μg/mL, respectively [64]. Ilicicolin C (196) and ilicicolin F (198) obtained from phytopathogenic fungus Nectria galligena were active against Pseudomonas syringae with IC50 values of 28.5 and 28.5 μg/mL, respectively [63].

Both nectrianolins A (199) and B (200) were sesquiterpene-epoxyclohexenone conjugates isolated from Nectria pseudotrichia 120-1NP [73].

Chalmicrin (202), a mannitol ether of methylated monocyclofarnesol, was isolated from Nectria sp. HLS206 that was associated with the marine sponge Glliodes carnosa [81]. This compound was previously isolated from the fungus Chalara microspora [84].

Both MBJ-0009 (207) and MBJ-0010 (208), which were related to the eremophilane class and isolated from the saprobic fungus Nectria sp. f26111, showed moderate cytotoxic activity against human ovarian adenocarcinoma SKOV-3 with the IC50 values of 24.7 and 11.2 mM, respectively [82].

Taxol (generic name paclitaxel, 209), the well-known anticancer agent, was isolated from the endophytic fungus Gliocladium sp. from Taxus baccata [83]. The backbone of taxol (209) is a diterpenoid, and the side chain is phenylalanine-derived. Both diterpenoid and phenylpropanoid pathways are required for taxol biosynthesis. Taxol (209) was found in both plants [85] and fungi [86]. It is a result of the co-evolution of plants and fungi in secondary metabolism [75].

5. Miscellaneous Metabolites and Their Biological Activities

The miscellaneous metabolites mainly including phenolics and fatty acids isolated from Clonostachys fungi are listed in Table 4, and their structures are shown in Figure 15.

Table 4.

Miscellaneous metabolites in Clonostachys fungi and their biological activities.

Metabolite Name Fungal Species Biological Activity Ref.
4-Hydroxybenzoic aldehyde (210) Gliocladium roseum CGMCC 3.3657 - [87]
4-Hydroxy-benzoic acid (211) Gliocladium roseum CGMCC 3.3657 - [87]
3,4-Dihydroxy-benzoic acid (212) Gliocladium roseum CGMCC 3.3657 - [87]
3,5-Dihydroxy-benzoic acid (213) Gliocladium roseum CGMCC 3.3657 - [87]
2,5-Dimethoxy-3,6-dimethylbenzene-1,4-diol (214) Nectria coryli - [54]
3,5-Dihydroxybenzyl alcohol (215) Nectria sp. B-13 - [34]
3,5-Dihydroxytoluene (216) Nectria sp. B-13 - [34]
5-n-Heneicosylresorcinol (217) Gliocladium roseum YMF1.00133 Antinematodal activity [22]
Toluquinol (218) Nectria erubescens - [57]
Clonostach acid A (219) Clonostachys rosea B5-2 - [58]
Clonostach acid B (220) Clonostachys rosea B5-2 - [58]
Clonostach acid C (221) Clonostachys rosea B5-2 - [58]
2-Furoic acid (222) Bionectria sp. Y1085 - [17]
5-Hydroxymethyl furoic acid (223) Bionectria sp. Y1085 - [17]
2-Hydroxy-5-hydroxymethyl furan (224) Bionectria sp. Y1085 - [17]
3-(R)-Piliformic acid (225) Bionectria sp. - [28]
3-(S)-Piliformic acid (226) Nectria pseudotrichia Leishmanicidal activity [30]
6′-Acetoxy-piliformic acid (227) Nectria pseudotrichia Leishmanicidal activity [30]
5′,6′-Dehydropiliformic acid (228) Nectria pseudotrichia - [30]
Hypocrealesate (229) Nectria sp. HLS206 - [81]
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Figure 15.

Figure 15

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Miscellaneous metabolites isolated from Clonostachys fungi.

Four phenolic metabolites were isolated and identified as 4-hydroxybenzoic aldehyde (210), 4-hydroxybenzoic acid (211), 3,4-dihydroxybenzoid acid (212), and 3,5-dihydroxybenzoic acid (213) from Gliocladium roseum CGMCC 3.3657 [87].

5-n-Heneicosylresorcinol (217) was isolated from Gliocladium roseum YMF1.00133. After 24 h incubation, 5-n-heneicosylresorcinol (217) showed antinematodal activity against Caenothabditis elegans at 15 and 30 μg/mL, against Panagrellus redivivus at 50 and 80 μg/mL, and against Bursaphelenchus xylophilus at 200 and 180 μg/mL, respectively [22].

Five fatty acids named clonostach acids A (219), B (220), and C (221) were isolated from the endophytic fungus Clonostachys rosea B5-2 [58].

Three furan derivatives, named 2-furoic acid (222), 5-hydroxymethyl furoic acid (223) and 2-hydroxy-5-hydroxymethyl furan (224), were isolated from Bionectria sp. Y1085 [17].

Three piliformic acid derivatives were isolated from Nectria pseutrichia. Both 3-(S)-piliformic acid (226) and 6’-acetoxy-piliformic acid (227) were screened to show leishmanicidal activity [30].

6. Conclusions and Future Perspectives

In this mini-review, we summarized chemical structures, occurrences and biological activities of the secondary metabolites from Clonostachys fungi. The main metabolites belong to nitrogen-containing compounds, polyketides, and terpenoids. Some piperazines (i.e., bionetins, gliocladins and gliocladins and verticillins), polyketides (i.e., nectriaquinones, pesudonectrins, bionectriols, and nectriacids) and terpenoids (i.e., glisoprenins and ilicicolins), which were only isolated from Clonostachys fungi, exhibited obvious biological activities, such as antimicrobial, cytotoxic, antinematodal, and AChE inhibitory activities (Table 1, Table 2 and Table 3). Some metabolites, such as alternariol (86) sorbicillinoids, were also distributed in other groups of fungi. Some metabolites, such as cyclosporin A (12), cinnacidin (61), and taxol (209), have shown their medicinal and agricultural applications.

In order to search for new bioactive metabolites from Clonostachy fungi, some strategies, such as gene disruption, modification of the fermentation medium, co-cultivation and synthetic modification, have been proven to be effective. Gliocladiosins A (67) and B (68), as well as rogersonins A (69) and B (70) were alkaloid–polyketide hydrids isolated from gene disruption mutants of Clonostachys rogersoniana [32,33]. Fermentation of the Clonostachys rosea on white beans instead of rice afforded one γ-lactam clonostalactam (62) and two γ-lactones 3,5-dihydroxyfuran-2(5H)-one (141) and sapinofuranone B (142) that were not detected in the former extracts [11]. The apple juice supplemented solid rice media led to significant changes in the secondary metabolism of the fungus, Clonostachys rosea B5-2, and induced the production of four new compounds, (-)-dihydrovertinolide (144), clonostach acids A (219), B (220) and C (221) together with the known compound, (-)-vertinolide (143) [58]. Co-cultivation of the Bionectria sp. with either Bacillus subtilis or Streptomyces lividans resulted in the production of bionectriamines A (59) and B (60), and 6,8-dihydroxyisocoumarin-3-carboxylic acid (93) [28]. In addition, based on the isolated compounds, more bioactive compounds can be synthesized. A typical example was the synthesis of cinnacidin (61) analogs. Two new structural analogs of cinnacidin (61), namely (2S,3S)-2-[(3RS,3aSR,6aRS)-3-methoxy-4-oxo-3,3a,4,5,6,6a-hexahydropentalen-1-ylcarbamoyl]-3-methylvaleric acid and benzyl (2S,3S)-2-[(3RS,3aSR,6aRS)-3-methoxy-4-oxo-3,3a,4, 5,6,6a-hexahydro pentalen-1-ylcarbamoyl]-3-methylvalerate, have been synthesized. The synthetic compounds were highly phytotoxic on a range of weeds to show their potential application as an herbicide [29]. Furthermore, the phenolic sesquiterpenoids which are also called ascochlorin derivatives or ilicicolins were widely distributed in the fungi of genus Nectria (synonym: Clonostachys). The occurrence of these compounds further confirms the close chemotaxonomic relationships among the related Nectria species. Ilicicolin H (71) was considered to be of potential chemotaxonomic significance and could be used as the main chemotaxonomic marker of the Nectriaceae family [34]. Some piperazines, such as bionetins [16], gliocladins [21], gliocladines [23], glioperazines, and verticillins were also only isolated from the fungal species of Clonostachys. Their chemotaxonomic significance should be further verified.

Though major fungal species of Clonostachys fungi have been studied for their metabolites [1], the remaining fungi need to be revealed in detail. Moreover, the biological activities, structure–activity relationships, mechanisms of action, as well as biosynthesis of the metabolites from Clonostachys fungi need to be further investigated. Clarification of the metabolites of Clonostachys fungi could not only be in favor of discovering more compounds with novel structures and excellent biological activities, but also better understand the chemotaxonomy of the genus Clonostachys.

Author Contributions

Conceptualization, L.Z. and P.H; Writing—original draft preparation, P.H. and L.Z.; Writing—review and editing, D.L., X.Z., D.X. and B.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Key R&D Program of China (2017YFD0201105 and 2017YFD0200501).

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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